Substituted tetrahydropyridines and process therefor



United States Patent ICC 3,272,837

Patented Sept. 13, 1966 alkyl group at the 1-position followed by reduction with ,337 a metal hydride reducing agent yields substituted 1,2,5,6- SUBSTITUTED TETRAHYDROPYRIDINES AND tetrahydropyridines having the formula:

PROCESS THEREFOR Marshall D. Draper, Woodland Hills, Calif., assignor to Rexall Drug and Chemical Company, Los Angeles, 5 w a y Calif., a corporation of Delaware No Drawing. Filed Oct. 30, 1964, Ser. No. 407,846 13 Claims. (Cl. 260297) This application is a continuation-impart of my applilo cation entitled, Substituted Tetrahydropyridines and Process Therefor, Serial No. 371,791, filed June 1, 1964,

now abandoned, which is in turn a continuation-in-part Phen: frqmvalentsg P wm are descl'lbfid and of my application entitled, Substituted Tetrahydropyrclalmed In my app-hcatlon Senal 1 3 filed, mines, Serial 310,890, filed September 23 1963, 15 tember 23, 1963, now abandoned, ent1tled, Substituted now abandoned Indenopyridines and Process Therefor.

This invention relates to compositions of matter classimanner and Process of l and tied in the art of chemistry as substituted tetrahydropyriventlon be generally desqnbed so as to enable dines and to a process for their preparation a person skilled in the art of chemistry to make and use The invention sought -to be patented, in its product the Same E follows: composition aspect, is described as residing in the concept The reacllofl q q lsadlng to the embodl' of a chemical compound in which there is attached at the l mvenllon f lts product composmon P f l position of a 3 (a hydroxybenzyl) 4 pheny1 1,2,3,6 and depicting the invention sought to be patented 1n its tetrahydropyridine nucleus, a lower alkyl, lower alkenyl Procfiss aspect 15 Set forth as follows: or phenyl-lower alkyl group, and to its hereinafter dis- 0 closed equivalents. A

The invention sought to be patented, in its process 3 aspect, is described as residing in the concent of refluxing a 3-benzoyl-4-phenyl-1,2,3,6-tetrahydropyridine bearing a lower alkyl, lower alkenyl or phenyl-lower alkyl group at the l-position, or its hereinafter described equivalents, with an alkali metal aluminohydride reducing agent in the presence of aluminum chloride or with an alkali metal borohydride reducing agent thereby to form t the tangible embodiments of this invention in its product Starting Material composition aspect.

As used throughout the specification and claims, the term lower alkyl embraces both straight and branched chain alkyl radicals having from 1 to 6 carbon atoms for LiAlH AlCla OH example methyl, ethyl, n-propyl, isopropyl, n-hexyl, 2- 4 l ethylbutyl and the like; the term lower alkenyl denotes /H\/2\ a monovalen-t radical C H wherein n is an integer 1N R from 3 to 6, for example allyl, butenyl, hexenyl and the 4 5 like; the term phenyl-lower alkyl denotes a radical wherein phenyl is substituted for a hydrogen atom of a lower alkyl substituent, for example benzyl, phenethyl, amethyl benzyl, phenyl-n-propyl and the like; the term lower alkoxy denotes alkoxy groups containing from 1 to 6 carbon atoms, for example, methoxy, ethoxy, isopropoxy, n-butoxy, n-hexyloxy and the like and the term Final Ploduct halo embraces chloro, bromo, fluoro and iodo.

The tangible embodiments of this invention, in its product composition PF P inherent general The starting materials depicted hereinabove are readily physical characteristics of being SOlld crystalline rnaprepared by known chemical processes f example b terials. Spectral data and elemental analyses, taken todghydration f 1 R 3.ben y1 4 hydroxy-4 .pheny1piprigelhef With The afcremfintioned Physical Properties, the dines by heating with acetic anhydride and sulfuric acid, nature of the Starting materials and "511s mode of Starting materials wherein the benzoyl radical and/or wherein R is lower alkyl, lower alkenyl or phenyl-lower alkyl.

thesis, Positively Confirm the Structure of the compounds the phenyl radical at the 3- and 4-positions, respectively, Sought to be P of the tetrahydropyridine nucleus are nuclearly substi- The Tangible embodiments of this invfintion P tuted with one or more lower alkyl, lower alkoxy or the inherent pp 1156 characteristics of having halogen groups and/ or starting materials having a phenyl nificant pharmacological activity as diuretic agents as delower alkyl R-substituent in which the phenyl group is termined by recognized and accepted pharmac l gi al nuclearly substituted with one or more lower alkyl, lower test procedures, as well as being useful and valuable as alkoxy or halogen groups are prepared by analogous chemical intermediates in the production of other subprocesses and are the full equivalents of the specific startstituted tetrahydropyridines. For example, tosylation of ing materials depicted hereinabove. Their use in the the tangible embodiments of this invention having a lower foregoing reaction sequence results in the praparation of final products having the same utility as the specific final products depicted hereinabove.

The starting material is converted to the tangible embodiments of this invention by treatment with an alkali metal borohydride reducing agent, such as sodium or potassium borohydride, in the presence of an inert organic solvent such as methanol, ethanol, and the like, at from room temperature to the reflux temperature of the solvent, or by treatment with an alkali metal aluminohydride, such as lithium aluminum hydride, in combination with aluminum chloride, at reflux temperature in the presence of an inert organic solvent such as ether, dioxan, tetrahydrofuran and the like, resulting in the selective reduction of the carbonyl function in the benzoyl group at the 3-position of the starting materials to yield the substituted tetrahydropyridines which constitute the tangible embodiments of this invention in its product composition aspect. Upon completion of the reaction, residual reducing agent is decomposed by the addition of water and alkali and the product is recovered from the solution by conventional techniques of crystallization.

The tangible embodiments of this invention, in its product composition aspect, can, if desired, be converted into their non-toxic pharmaceutically acceptable acid-addition and quaternary ammonium salts. Salts which may be formed comprise, for example, salts with inorganic acids, such as the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate or the like. They may also comprise salts with organic acids, including monobasic acids such as the acetate or the propionate, and especially those with hydroxy organic acids and dibasic acids, such as the citrate, tartrate, malate, maleate and fumarate. Pharmaceutically, the salt will not be substantially more toxic than the compound itself and, to be acceptable, it should be able to be incorporated into conventional liquid or solid pharmaceutical media. Among the useful quaternary ammonium salts are those formed by such alkyl halides as methyl iodide, n-hexyl bromide and the like. Such pharmaceutically useful acid-addition and quaternary ammonium salts are the full equivalents of the bases from which they are derived and are included within the scope of this invention.

The tangible embodiments of this invention, either as free bases or in the form of a non-toxic pharmaceutically acceptable acid-addition or quaternary ammonium salt, can be combined with conventional pharmaceutical diluents and carriers, to form such dosage forms as tablets, capsules, solutions, suspensions, suppositories and the like.

The best mode contemplated by the inventor for carrying out this invention will now be set forth as follows:

The following example is illustrative of the selective reduction of the carbonyl group in the starting material by treatment with an alkali metal aluminohydride reducing agent in combination with aluminum chloride.

EXAMPLE 1 3- (a-hydroxybenzyl -methyl-4-phenyll ,2,3,6-tetrahydrpyridine Dissolve lithium aluminum hydride (1 g.) in ether (100 ml.) and add aluminum chloride (5.0 g.) cautiously with stirring. Slowly add to this mixture 3-benzoyl-1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (5.0 g.) and stir for 1 hour. Add water (60 ml.) dropwise with stir- :ring. During this addition most of the ether boils off. Basify the remaining aqueous mixture with ammonium hydroxide and filter. Digest the filter-cake thus obtained with three 100 ml. portions of hot chloroform. Wash the chloroform extracts with water, dry over anhydrous magnesium sulfate and remove the solvent in vacuo. Dry the product, which crystallizes during removal of the solvent, at 50 C. and 1 mm. Hg for 2 hours to yield 38 g. (77%) of crystalline product, M.P. 136-137 C.

Analysis.Calculated for C H NO: C, 81.68%; H, 7.58%; N, 5.01%. Found: C, 81.69%; H, 7.68%; N, 5.01%.

The following examples are illustrative of the selective reduction of the carbonyl group in the starting material by treatment with an alkali metal borohydride reducing agent.

EXAMPLE 2 3-(a-hydroxy-p-methylbenzyl)-1-metlzyl-4- (p-methylphenyl) -1,2,3,6-tetrahydropyridine 1 methyl 3 (p methylbenzoyl) 4 (p methylphenyl)-1,2,3,6-tetrahydropyridine (18 g., 0.056 mole) is dissolved in absolute ethanol (150 ml.) and sodium borohydride (2.2 g., 0.058 mole) is added. The solution is allowed to remain at 35 C. for about 2 hours, with intermittent gentle shaking, and then is heated to reflux temperature for 4 hours. The mixture is cooled to room temperature, about 10 ml. of water is added and the ethanol is removed under reduced pressure. The residue is taken up in ether (200 ml.) and 4% aqueous base (150 ml.) is added. The aqueous phase is twice extracted with ether m1. portions) and the extracts washed with water (100 ml.). The extract is then dried over anhydrous magnesium sulfate, filtered and concentrated. The product crystallizes on cooling and is recrystallized from ether/ petroleum ether to yield 12.8 g. (75%) of crystals, M.P. -122" C.

Analysis.Calculated for C H NO: C, 82.20%; H, 8.22%; N, 4.57%. Found: C, 82.18%; H, 8.05%; N, 4.54%.

EXAMPLE 3 3-(a-hydroxy-p-fluorobenzyl)-1-mcthyl-4-(pfluorophenyl) -1,2,3,6-tetrahydropyridine 1 methyl 3 (p fluorobenzoyl) 4 p (fluorophenyl)-1,2,3,6-tetrahydropyridine (14.4 g., 0.0461 mole) and sodium borohydride (1.8 g., 0.0475 mole) are dissolved in ethanol ml.) and the solution is refluxed for 3 hours. Water (10 ml.) is then added and the ethanol is removed under reduced pressure. The residue is taken up in ether (250 ml.), 2 N sodium hydroxide (100 ml.) is added and, after shaking, the aqueous phase is extracted 3 times with ether (75 ml. portions). The combined ether extracts are washed with water, dried over anhydrous magnesium sulfate and filtered. The solution is concentrated and cooled. The crystalline product which appears upon cooling is recovered by filtrat1on, washed with petroleum ether and dried in vacuo to yield 7.75 g. (53%) product, M.P. 162 C.

Analysis.Calculated for C H F NO: C, 72.50%; H, 6.03%; N, 4.45%. Found: C, 72.30%; H, 6.04%; N, 4.52%.

EXAMPLE 4 3- (a-lzydroxy-p-methoxybenzyl) -1-methyl-4- (p-methgxyph enyl)-1,2,3,6-terlrahydropyridine 1-methyl-3-(p-methoxybenzoyl) 4 p-methoxyphenyl- 1,2,3,6-tetrahydropyridine (19.5 g., 0.058 mole) and sodium borohydride (2.4 g., 0.0637 mole) are mixed with methanol (100 ml.) and the mixture is refluxed for 30 minutes. The mixture is cooled to room temperature, water (25 ml.) is added and the solution concentrated. The residual oil emulsion is mixed with 1 N sodium hydroxide (25 ml.). The aqueous phase is extracted with ether. The product is then recovered by filtration and crystallization in a yield of 13.0 g. (66%), M.P. 101 C.

Analysis.Calculated for C H NO C, 74.40%; H, 7.43%; N, 4.13%. Found: C, 74.53%; H, 7.37%; N, 3.99%.

EXAMPLE 5 1-allyl-3-(oc-hydnoxy-p-chl0r0benzyl-4-(p-chlorophenyl 1,2,3,6-tetrahydropyridine 1-allyl-3-(p-chlorobenzoyl) 4 (p chlorophenyl)- 1,2,3,6-tetrahydropyridine (8 g., 0.0215 mole) and sodium. borohydride (0.9 g., 0.0248 mole) are refluxed in a mixture of absolute ethanol (50 ml.) and tetrahydrofuran ml.) for 2 hours. After cooling, water and base (30 ml. 1 N sodium hydroxide) are added to decompose residual reducing agent and the product is recovered and isolated by extraction, filtration and crystallization in a yield of 3.4 g., M.P. 151152.5 C.

Analysis.-Calculated for C H NOCl C, 67.50%; H, 5.66%; N, 3.75%; Cl, 18.95%. Found: C, 67.40%; H, 5.74%; N, 3.90%; Cl, 18.77%.

EXAMPLE 6 1-allyl-3- (a-hydroxy-p-methvxybenzyl) -4- (pmethoxyphenyl) -1 ,2,3,6-tetrahydropyridine 1-allyl-3-(p-methoxybenzoyl) 4 (p methoxyphenyl)-1,2,3,6-tetrahydropyridine (6.0 g., 0.016 mole) is dissolved in 95% ethanol (60 ml.) and sodium borohydride (0.62 g., 0.016 mole) is added with vigorous stirring. A precipitate forms immediately. Stirring of the mixture in continued at room temperature for an additional 30 minutes after the addition of 95% ethanol (20 rnl.). Water is added and the product is recovered by filtration, washed with water and dried. Yield is 5.5 g. (91%), M.P. 92-93 C.

Analysis.-Ca-lculated for C23H27NO3: C, 75.59%; H, 7.46%; N, 3.84%. Found: C, 76.07%; H, 7.87%; N, 3.84%.

EXAMPLE 7 1-benzyl-3-(a-hydroxy-p-methoxybenzyl)-4-(pmethoxyphenyl) -1,2,3,6-tetrahydr0pyridine l-benzyl 3 (p methoxybenz-oyl) 4 (p-methoxyphenyl)-1,2,3,6-pyrid-ine (9.8 g., 0.0237 mole) is dissolved in tetrahydrofurane (100 m1.) and sodium borohydride (0.95 g., 0.025 mole) is added. The mixture is stirred at room temperature for 1 /2 hours and then at reflux for 2 /2 hours. Absolute ethanol (50 ml.) is added and the mixture refluxed for an additional hour. After cooling the solvents are removed under reduced pressure. To the residue is added 1 N sodium hydroxide (50 ml.) and the product is then extracted out with chloroform (three 75 ml. portions). The combined extracts are washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to an oil. Crystals form after petroleum ether is added and are recovered in a yield of 8.25 g., M.P. 102106 C.

Analysis.Calculated for C H NO C, 78.20%; H, 7.05%; N, 3.37%. Found: C, 78.47%; H, 7.01%; N, 3.35%.

The subject matter which the applicant regards as his invention is particularly pointed out and distinctly claimed as follows:

1. l-lower alkyl 3 (oz hydroxybenzyl) 4 phenyl- 1,2,3,G-tetrahydropyridine.

2. l-lower alkenyl 3 (a hydroxybenzyl) 4-phenyl 1,2,3,6-tetrahydropyridine.

3. l-phenyl-lower alkyl 3 (a hydroxybenzyl)-4- phenyl-1,2,3,6-tetrahyd-ropyridine.

4. 3 (a hydroxybenzyl) 1 methyl 4 phenyl- 1,2,3,6-tetrahydropyridine.

5. 3 (a hydroxy p methylbenzyl) 1 methyl-4- (p-methylphenyl) -1,2,3 ,6-tetrahydropyridine.

6. 3 (a hydroxy p fluorobenzyl) 1 methyl-4- (p-fluorophenyl) -l ,2,3 ,6-tetrahydropyridine.

7. 3-(a-hydroxy-p-methoxybenzyl)-1 methyl 4 (pmethoxyphenyl) 1,2, 3 ,6-tetrahydropyridine.

8. 1 allyl 3 (0c hydroxy p chlorobenzyl) 4- (p-chlorophenyl)-1,2,3,6-tetrahydropyridine.

9. 1 allyl 3 (oz hydroxy p methoxybenzyl 4- (p-methoxyphenyl) -1,2,3,6-tetrahydropyridine.

10. 1 benzyl 3 (0c hydroxy 1p methoxybenzyl)- 4- (p-methoxyphenyl -1,2,3 ,6-tetrahydropyridine.

11. A method of selectively reducing the carbonyl group of a 3 benzoyl 4 phenyl 1,2,3,6 tetrahydropyridine to form a 3 (0c hydroxybenzyl) 4 phenyl 1,2,3,6- tetrahydropyridine which comprises treating said 3-benzoyl 4 phenyl 1,2,3,6 tetrahydropyridine with a member selected from the group consisting of an alkali metal borohydride and an alkali metal aluminohydride in combination with aluminum chloride.

12. A method according to claim 11 wherein said alkali metal borohydride is sodium borohydride.

13. A method according to claim 11 wherein said alkali metal aluminohydride is lithium aluminum hydride.

No references cited.

WALTER A. MODANCE, Primary Examiner.

ROBERT T. BOND, Assistant Examiner. 

1. 1-LOWER ALKYL - 3 - (A - HYDROXYBENZYL) - 4 - PHENYL1,2,3,6-TETRAHYDROPYRIDINE. 